November 2013

FoxO3 and Sirt6 play an important role in regulating SREBP-2 and cholesterol homeostasis

Cholesterol is an essential component of the cell membrane and serves as a precursor for the biosynthesis of a number of molecules found in eukaryotes, such as sterol hormones, bile acid and vitamin D. While cholesterol is crucial for eukaryotes to function, hypercholesterolemia, or abnormally high cholesterol levels, is strongly associated with heart attack, stroke and peripheral vascular disease. Therefore, cholesterol levels must be maintained and regulated carefully.
 
Because of cholesterol’s importance in cell structure and function and its role in numerous biological pathways, understanding how host systems regulate cholesterol synthesis is a major focus of research. An important regulator for cholesterol biosynthesis is sterol regulatory element binding protein 2, or SREBP-2. Synthesis of cholesterol is controlled in a homeostatic manner and is linked to the levels of cholesterol present; SREBP-2 plays a crucial role in regulating this process. SREBP-2 functions as a transcription factor to control the expression of a number of genes involved in cholesterol biosynthesis, and until recently, the epigenetic regulation of this molecule gene was not understood.

X. Charlie Dong
X. Charlie Dong

In a recent article in the Journal of Lipid Research, a research team led by X. Charlie Dong at Indiana University School of Medicine reported that Sirt6 plays a critical role in the regulation of SREBP-2. Loss of Sirt6 results in elevated SREBP-2 and increased cholesterol levels, while overexpression of Sirt6 decreases SREBP-2 and cholesterol levels. Moreover, the researchers found that Sirt6 interacts with forkhead box O3 transcription factor 3, or FoxO3 (which has been linked to cholesterol synthesis in the liver) to modify the SREBP-2 gene locus and regulate the expression of the SREBP-2 gene. In addition, the authors found that overexpression of Sirt6 can improve hypercholesterolemia in mice.
 
According to the Centers for Disease Control and Prevention and the World Health Organization, heart disease is the leading cause of death in the United States, and cardiovascular diseases are the leading cause of death worldwide. The findings of this study not only improve our understanding of cholesterol homeostasis but may have a lasting impact on the fight against cardiovascular diseases.

Kyeorda KempKyeorda Kemp (kyeordakemp2010@u.northwestern.edu) is a postdoctoral researcher at Northwestern University.


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